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Biomolecules
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Signaling Pathways as Therapeutic Targets for Cancer
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Signaling Pathways as Therapeutic Targets for Cancer

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 December 2025) | Viewed by 9471

Special Issue Editor

Dr. Fabian Benencia

E-Mail Website
Guest Editor
Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Academic Research Center 202C, Ohio University, Athens, OH 45701, USA
Interests: tumor immunology; dendritic cells; macrophages; ovarian cancer; breast cancer; oncolytic viruses
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The hallmarks of cancer, based on Weinberg and Hannahan’s original classification, currently include several features such as activating invasion and metastasis, genome instability and mutation, resisting cell death, deregulating cellular metabolism, and sustaining proliferative signaling, among others. In all of these processes, cell signal transduction is fundamental. It has been largely known that signaling pathways are deregulated in many tumors and thus have been targeted in antitumor therapies. Key signaling pathways that are altered in cancer cells are the Wnt/β-Catenin pathway, the PIK3/AKT/mTOR pathway, the MAPK pathway, the NOTCH pathway, and the NF-kB pathway. In addition to these, other important signaling pathways involved include, but are not limited to, the p53 signaling pathway, the TGF-β pathway, the Hedgehog pathway, and pathways involved in cancer metabolism (e.g., glucose or fatty acid metabolism), epigenetic mechanisms, and immune responses. Signaling pathways in cancer are targeted via specific antibodies, small molecules (e.g., kinase inhibitors), or genetic approaches. Therapies include the use of single or combinatorial approaches, but resistance and toxicity are some of the challenges that remain to be solved. This Special Issue will focus on novel therapeutic approaches to target signaling pathways in cancer, with emphasis on recent discoveries, combinatorial approaches, new targets, and promising new drugs.

Dr. Fabian Benencia
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cancer signaling pathways
  • cancer metabolism
  • small molecules
  • anticancer antibodies
  • tumor models
  • combinatorial therapies

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Published Papers (5 papers)

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Research

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24 pages, 3370 KB  
Article
Exogenous Selenoprotein V Induces Apoptosis in Murine Testicular Teratoma Cells via Mitochondrial Dysfunction and ROS Overproduction
by Egor A. Turovsky and Elena G. Varlamova
Biomolecules 2025, 15(12), 1733; https://doi.org/10.3390/biom15121733 - 12 Dec 2025
Cited by 2 | Viewed by 626
Abstract
This study explores the effects of exogenous SELENOV on cellular migration, viability, mitochondrial function, ROS production, and Ca2+ signaling in mouse fibroblast L-929 and testicular teratoma F-9 cells. In scratch assays, 50–100 µg/mL SELENOV significantly inhibited F-9 cell migration after 48 h, [...] Read more.
This study explores the effects of exogenous SELENOV on cellular migration, viability, mitochondrial function, ROS production, and Ca2+ signaling in mouse fibroblast L-929 and testicular teratoma F-9 cells. In scratch assays, 50–100 µg/mL SELENOV significantly inhibited F-9 cell migration after 48 h, while in L-929 fibroblasts, only 100 µg/mL had a suppressive effect. Viability assays revealed strong cytotoxicity in F-9 cells. Critically, at a dose of 50 µg/mL (where the corresponding volume of solvent buffer alone was non-toxic), SELENOV reduced survival to 19%, triggering late apoptosis in 76% of cells, whereas in L-929 cells, comparable effects required 100 µg/mL. Mitochondrial depolarization (JC-1/Rhodamine-123 assays) was pronounced in F-9 cells even at 50 µg/mL, while L-929 cells responded only to 100 µg/mL. Similarly, 50 µg/mL SELENOV induced significant ROS overproduction in F-9 but not in L-929 cells, correlating with upregulated NOX1, NOX4, GPX3, and GPX4 expression. Ca2+ imaging showed dose-dependent [Ca2+]ᵢ elevation, with 50 µg/mL SELENOV inducing a sustained rise in F-9 cells, whereas L-929 cells required higher doses. Strikingly, 50 µg/mL SELENOV in F-9 cells downregulated BCL-2 and BCL-xL while upregulating pro-apoptotic BAX and PUMA, suggesting selective activation of intrinsic apoptosis. These results demonstrate that F-9 cancer cells are significantly more sensitive to SELENOV than normal fibroblasts, with 50 µg/mL sufficient to trigger mitochondrial dysfunction, oxidative stress, and apoptosis. The findings highlight SELENOV’s potential as a targeted anticancer agent, particularly for germ cell tumors. Full article
(This article belongs to the Special Issue Signaling Pathways as Therapeutic Targets for Cancer)
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16 pages, 2363 KB  
Article
BUB1 an Overexpressed Kinase in Sarcoma: Finding New Target Therapy for Osteosarcoma, Liposarcoma, Synovial Sarcoma, and Leiomyosarcoma
by Mercedes Olvera-Valencia, Fernando Luna-Maldonado, Joselyn Juarez-Reyes, Alejandro Lopez-Saavedra, Jossimar Coronel-Hernandez, Oliver Millan-Catalan, Daniel Guzman-Gomez, Frida Rodríguez-Izquierdo, Luis A. Herrera, David Francisco Cantú-De León, Carlos Perez-Plasencia and Eloy-Andres Pérez-Yepez
Biomolecules 2025, 15(7), 1046; https://doi.org/10.3390/biom15071046 - 18 Jul 2025
Cited by 3 | Viewed by 2123
Abstract
Sarcomas are heterogeneous mesenchymal tumors, and their pharmacological treatment remains challenging due to the high toxicity and poor efficacy of current therapies. This study aimed to identify common overexpressed kinases in the four most frequent sarcoma subtypes to establish novel therapeutic targets. A [...] Read more.
Sarcomas are heterogeneous mesenchymal tumors, and their pharmacological treatment remains challenging due to the high toxicity and poor efficacy of current therapies. This study aimed to identify common overexpressed kinases in the four most frequent sarcoma subtypes to establish novel therapeutic targets. A bioinformatics approach using patient-derived gene expression data sets identified overexpressed kinases shared across these sarcoma types. Later, BUB1 was determined as the kinase consistently overexpressed across the osteosarcoma, liposarcoma, leiomyosarcoma, and synovial sarcoma. Moreover, the role of this kinase was further validated through molecular and functional assays, including pharmacological inhibition in cell lines derived from the four sarcoma subtypes. BUB1 inhibition reduced the phosphorylation of AKT and H2A proteins, precluded cell proliferation, and inhibited colony formation in sarcoma cells. Finally, overall survival analysis highlighted a strong correlation between high BUB1 expression and poorer survival rates in sarcoma patients. Altogether, these findings underscore the potential of BUB1 as a therapeutic target and prognostic marker in sarcomas. Targeted inhibition of BUB1 may provide a novel strategy to reduce tumor growth and improve outcomes for patients with bone and soft tissue sarcomas. Full article
(This article belongs to the Special Issue Signaling Pathways as Therapeutic Targets for Cancer)
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24 pages, 11315 KB  
Article
Enhancing Ferroptosis in Lung Adenocarcinoma Cells via the Synergistic Action of Nonthermal Biocompatible Plasma and a Bioactive Phenolic Compound
by Sabnaj Khanam, Young June Hong, Youngsun Kim, Eun Ha Choi and Ihn Han
Biomolecules 2025, 15(5), 691; https://doi.org/10.3390/biom15050691 - 9 May 2025
Cited by 3 | Viewed by 2625
Abstract
Para-coumaric acid (p-CA) is a phenolic compound that has antioxidant, anti-inflammatory, and anticancer properties which make it potential for cancer treatment. However, its effectiveness has been limited by poor solubility, rapid metabolism, and poor absorptivity. Nonthermal biocompatible pressure plasma (NBP) has gained attention [...] Read more.
Para-coumaric acid (p-CA) is a phenolic compound that has antioxidant, anti-inflammatory, and anticancer properties which make it potential for cancer treatment. However, its effectiveness has been limited by poor solubility, rapid metabolism, and poor absorptivity. Nonthermal biocompatible pressure plasma (NBP) has gained attention as a cancer treatment due to its ability to generate reactive oxygen and nitrogen species (RONS), inducing oxidative stress that damages cancer cells. This study aimed to investigate the combined effect of NBP and p-CA on the induction of ferroptosis in lung adenocarcinoma via the GPX4, xCT, and NRF2 pathways. H460 and A549 lung adenocarcinoma cells as well as normal lung cells (MRC5) were treated with p-CA, NBP, and their combination. Cell movement, intracellular RONS levels, and lipid peroxidation, along with apoptosis and ferroptosis-related gene expression, were evaluated by co-treatment. Co-treatment also significantly elevated NO2−, NO3−, and H2O2 levels and reduced cancer cell (H460, A549) viability (26, 31%) without affecting normal cells MRC5 (7%). Elevated MDA levels and changed expression of ferroptotic proteins indicated mitochondrial dysfunction, oxidative damage, lipid peroxidation, and DNA damage, which resulted in the induction of ferroptosis. These findings reveal a novel ferroptosis mechanism, emphasizing co-treatment for delivering bioavailable natural anticancer drugs. Full article
(This article belongs to the Special Issue Signaling Pathways as Therapeutic Targets for Cancer)
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Review

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33 pages, 2534 KB  
Review
Metformin—A Type 2 Diabetes Mellitus Drug—And Ovarian Cancer: Anticancer Mechanisms and Therapeutic Implications
by Emma Sielski, Al-Noumani Shuhd, Ella Bower, Kate Cunningham, Grace Beidel, Alissa Luchianova, Maria Cecilia Courreges and Fabian Benencia
Biomolecules 2026, 16(3), 413; https://doi.org/10.3390/biom16030413 - 11 Mar 2026
Viewed by 962
Abstract
Ovarian cancer is a devastating disease that is often diagnosed in the late stages. The typical therapeutic approach includes surgery plus cytotoxic drugs such as carboplatin and paclitaxel. In recent years, the advent of poly ADP-ribose polymerase (PARP) inhibitors such as olaparib has [...] Read more.
Ovarian cancer is a devastating disease that is often diagnosed in the late stages. The typical therapeutic approach includes surgery plus cytotoxic drugs such as carboplatin and paclitaxel. In recent years, the advent of poly ADP-ribose polymerase (PARP) inhibitors such as olaparib has offered additional treatment opportunities for patients with BRCA mutations or homologous recombination deficiencies. Nevertheless, resistance to therapy usually occurs, leading to poor overall survival. Therefore, novel treatments are needed for this disease. One of the obstacles to successful treatment is the highly immunosuppressive nature of the ovarian cancer microenvironment. Recent strategies for the treatment of ovarian cancer and other types of cancer involve targeting the metabolism of cancer cells and other cells of the tumor microenvironment. One drug that has been investigated both in preclinical studies and clinical trials as an antitumor agent is metformin. This drug, typically used for the treatment of type-2 diabetes for its capability to lower blood glucose, can directly affect cancer cell growth and survival by activating the AMPK (adenosine monophosphate-activated protein kinase) pathway. Furthermore, it can affect the phenotype of other cells of the tumor microenvironment such as macrophages and T cells. In this review, we summarize the main characteristics of ovarian cancer and describe preclinical studies and clinical trials involving metformin as a therapeutic agent for this disease. Full article
(This article belongs to the Special Issue Signaling Pathways as Therapeutic Targets for Cancer)
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18 pages, 819 KB  
Review
Discoidin Domain Receptors in Tumor Biology and Immunology: Progression and Challenge
by Heng Zhang, Wenlong Chen, Haitao Zhu and Hsiang-i Tsai
Biomolecules 2025, 15(6), 832; https://doi.org/10.3390/biom15060832 - 7 Jun 2025
Cited by 3 | Viewed by 2263
Abstract
The onset and progression of tumors involve intricate, multifactorial processes. A key component in tumor evolution is the dynamic interaction between cancer cells and the extracellular matrix (ECM). Discoidin Domain Receptors (DDRs), a unique class of collagen-activated receptor tyrosine kinases, serve as critical [...] Read more.
The onset and progression of tumors involve intricate, multifactorial processes. A key component in tumor evolution is the dynamic interaction between cancer cells and the extracellular matrix (ECM). Discoidin Domain Receptors (DDRs), a unique class of collagen-activated receptor tyrosine kinases, serve as critical mediators of cell-ECM communication. Recent studies have uncovered their significant roles in modulating diverse cancer-related processes, including immune responses, cell proliferation, apoptosis, differentiation, metabolic reprogramming, metastasis, and resistance to therapy. This review begins with an overview of the discovery, structural features, and canonical and non-canonical functions of DDRs. It then focuses on the reciprocal regulation between DDRs and collagen in the tumor microenvironment, highlighting how this interplay contributes to cancer progression. Furthermore, we explore the involvement of DDRs in reshaping the tumor immune microenvironment and their influence on various aspects of cancer cell biology. Finally, we summarize the current advances in therapeutic strategies targeting DDRs, offering insights into their potential as biomarkers and drug targets in cancer treatment. Full article
(This article belongs to the Special Issue Signaling Pathways as Therapeutic Targets for Cancer)
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